2,4,5-trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivatives

ABSTRACT

2,4,5-Trihalogenobenzene derivatives of the formula ##STR1## in which R is --COOH, --COCl, --COF, --CN, --CONH 2 , --CH 2  OH, --CH 2  Cl, --CHCl 2 , --CCl 3  or --CHO, 
     R 1  is H, Cl or F, and 
     R 2  is Cl or F, 
     it only being possible for R 1  or R 2  to be F, and processes for their preparation starting from benzonitriles reacted with potassium fluoride. The novel compounds are intermediates for antibacterials such as quinolone carboxylic acids.

This application is a divisional, of application Ser. No. 08/284,331,filed Aug. 2, 1994, now abandoned which is a division of Ser. No.07/968,603, filed Oct. 29, 1992, issued to U.S. Pat. No. 5,362,909;which is a division of Ser. No. 07/763,027, filed Sep. 20, 1991, issuedto U.S. Pat. No. 5,200,548; which is a division of Ser. No. 07/459,876,filed Jan. 2, 1990, issued to U.S. Pat. No. 5,072,038; which is acontinuation of Ser. No. 06/735,502, filed May 17, 1985, now abandoned.

The present invention relates to 2,4,5-trihalogeno- and2,3,4,5-tetrahalogenobenzene derivatives and process for theirpreparation. The compounds according to the invention are valuableintermediates for the synthesis of highly active antibacterialmedicaments.

2,4,5-Trihalogeno- and 2,3,4,5-tetrahalogenobenzene derivatives of theformula (I) ##STR2## in which R represents --COOH, --COCl, --COF, --CN,--CONH₂, --CH₂ OH, --CH₂ Cl, --CHCl₂, --CCl₃ or --CHO,

R¹ represents H, Cl or F and

R² represents Cl or F,

it only being possible for R¹ or R² to be F, have been found.

The following may be particularly mentioned: 2,4,5-trifluorobenzoylfluoride; 2,3,4-trifluoro-5-chlorobenzoyl fluoride;2,4,5-trifluoro-3-chlorobenzoyl chloride;2,4-difluoro-3,5-dichlorobenzoyl fluoride.

It has also been found that the 2,4,5-trihalogeno- and2,3,4,5-tetrahalogenobenzene derivatives of the formula (I) ##STR3## inwhich R represents --COOH, --COCl, --COF, --CN, --CONH₂, --CH₂ OH, --CH₂Cl, --CHCl₂, --CCl₃ or --CHO,

R¹ represents H, Cl or F and

R² represents Cl or F,

it only being possible for R¹ or R² to be F, are obtained by reacting2,3,4,5-tetrachlorobenzonitrile with potassium fluoride in a solvent atelevated temperature, and converting the resulting nitriles into thecompounds of the formula (I) in a manner known per se.

It has also been found that 2,3,4,5-tetrahalogenobenzene derivatives ofthe formula (II) ##STR4## in which R' represents --COCl or --COF, and

R¹ represents Cl or F,

can be obtained by reacting 2,3,4,5-tetrachlorobenzoyl chloride or2,3,4,5-tetrachlorobenzoyl fluoride (see European Patent No. 57,844),where appropriate after fluorination with hydrofluoric acid, withpotassium fluoride in a solvent at elevated temperature.

The quantity of potassium fluoride to be used depends on the number ofchlorine atoms which are to be exchanged. At least one mole of KF isused, but in general 1.1-1.5 mole, for 1 chlorine atom. A maximum of 2moles of KF is used for 1 chlorine; beyond this, the quantity of KF hasvirtually no effect on the degree of fluorination, and the processbecomes uneconomic. However, it is possible to save part of the costlyKF when the 2,3,4,5-tetrachlorobenzoyl chloride is previouslyfluorinated with hydrofluoric acid, and the 2,3,4,5-tetrachlorobenzoylfluoride, which results in virtually quantitative yield from thisreaction, is used for the Cl/F exchange reaction with KF. Because of thegreater activation by the more electronegative fluorocarbonyl group, itsgreater thermal stability, and the reduced load of KCl in the reactionmixture, this two-stage fluorination leads to an overall improvement inthe balance of the nuclear fluorination.

The solvents which can be used for the nuclear fluorination are theinert solvents known for fluorination reactions, for exampledimethylformamide, dimethyl sulphoxide, N-methylpyrrolidone, diethylsulphone etc. However, tetramethylene sulphone (sulpholane) isparticularly preferably used.

The reaction temperature is between 160° and 260° C., depending on thedesired degree of fluorination. While product containing no fluorine inthe nucleus is still found at the lower temperature, a very evidentproportion of the known 2,3,4,5-tetrafluorobenzoyl fluoride is alreadyproduced at the higher temperatures (see German Patent Application P 3318 145, corresponding to U.S. application Ser. No. 603,480 filed Apr.24, 1984, now pending).

Because of the thermal instability of the tetrahalogenobenzoyl halidespresent in the reaction mixture--preferential formation ofoctahalogenobenzophenones--it has proved to be advantageous to removethe desired reaction product continuously from the reaction space bydistillation during the fluorination reaction. This is advantageouslycarried out via a fractionating column, continuously adjusting thedistillation pressure to the partial pressure of the fluorinationmixture.

It has also been found that 2,4,5-trifluoro-3-chlorobenzoyl chloride canbe obtained by reacting 2,4,5-trifluorobenzoyl chloride to give2,4,5-trifluoro-3-chlorobenzoic acid and reacting the latter withthionyl chloride. The 2,4,5-trifluorobenzoic acid required as startingmaterial for this has already been disclosed [J. I. de Graw, M. Cory, W.A. Skinner, J. Chem. Eng. Data 13, 587 (1968)]. Its preparationaccording to this literature citation is carried out, in very pooryield, from 2-amino-4,5-difluorobenzoic esters by NH₂ /F exchange in themanner of a Balz-Schiemann reaction. However,2,4-dichloro-5-fluorobenzoyl chloride has been disclosed in DE-OS(German Published Specification) 3,142,856=U.S. Pat. No. 4,439,620. Ithas now also been found that from this, by fluorination with KF in asolvent, preferably tetramethylene sulphone, at temperatures from 180°to 230° C., the new 2,4,5-trifluorobenzoyl fluoride is obtained in astraightforward manner and in good yield, and the latter is convertedvirtually quantitatively into 2,4,5-trifluorobenzoic acid by alkalinehydrolysis.

The chlorination of the 2,4,5-trifluorobenzoic acid is carried out inthe melt, under pressure and/or in a solvent, for examplechlorosulphonic acid or oleum, in the presence of halogen transferagents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid isobtained in this reaction. However, since the reaction mixture stillcontains unchanged starting material and some2,4,5,-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated,without intermediate isolation, with thionyl chloride. The desired2,4,5-trifluoro-3-chlorobenzoyl chloride is then obtained by fractionaldistillation. However, it is more favorable to carry out the separationby distillation of the acid fluorides.

The functionalization of the nitriles to give the corresponding acidhalides is carried out by, for example, hydrolysis to the carboxylicacid and conversion into acid chlorides using thionyl chloride. The acidfluorides are then obtained from the acid chlorides by reaction with thefluorinating agents, for example anhydrous hydrofluoric acid or alkalimetal fluorides. Conversely, if it is desired to prepare the acidchloride from an acid fluoride, then this is carried out by reactionwith SiCl₄, where appropriate in the presence of catalytic quantities ofaluminum chloride. Halogen-substituted benzyl alcohols can be preparedin a smooth reaction from the acid halides, especially well from theacid fluorides, by reduction with sodium borohydride.

From the halogenated benzyl alcohols, using thionyl chloride thecorresponding benzyl chlorides are obtained in virtually quantitativeyield, and the latter can undergo further stepwise chlorination withgaseous chlorine to give the corresponding benzal chlorides andbenzotrichlorides.

The halogenated benzaldehydes are obtained by, preferably acid,hydrolysis of the halogenated benzal chlorides, while correspondinghydrolysis of the halogenated benzotrichlorides provides both thecorresponding acid chlorides and the acids.

The compounds according to the invention are intended for use asstarting materials for the synthesis of medicaments.

The compounds according to the invention can be converted, for example,into highly active antibacterial1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacids. The synthesis can be carried out by, for example, the followingscheme, using 5-chloro-2,3,4-trifluorobenzoyl fluoride as the startingmaterial. ##STR5##

More precisely and in detail the compounds obtainable by conversion ofthe compounds according to the present invention are described in thefollowing. The compounds which are not subject matter of the presentinvention are new7-amino-1-cyclopropyl-6,8-dihalogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylicacids of the formula (I') ##STR6## in which X¹ and X², which can beidentical or different, represent chlorine or fluorine, but cannot bothbe fluorine, and

R³ and R⁴, together with the nitrogen atom to which they are bonded,form a 5- or 6-membered heterocyclic ring which can contain in addition,as ring member, the atoms or groups --O--, --S--, --SO--, --SO₂ --,<N--R⁵ or --CO--N^(I) --R⁵ and which can optionally be substituted onthe carbon atoms once to three times by C₁ --C₄ --alkyl, phenyl orcyclohexyl, each of which is optionally substituted once to three timesby chlorine, fluorine, bromine, methyl, phenyl, hydroxyl, methoxy,benzyloxy, nitro or piperidino, 2-thienyl, hydroxyl, alkoxy having 1 to3 carbon atoms, amino, methylamino or ethylamino,

R⁵ representing hydrogen, a branched or unbranched alkyl, alkenyl oralkinyl group having 1 to 6 carbon atoms which can optionally bysubstituted by one or two hydroxyl, alkoxy, alkylamino or dialkylaminogroups having 1 to 3 carbon atoms for an alkyl radical, the cyano group,or the alkoxycarbonyl group having 1 to 4 carbon atoms in the alcoholmoiety, a phenylalkyl group which is optionally substituted in thephenyl radical and has up to 4 carbon atoms in the aliphatic moiety, aphenacyl radical which is optionally substituted once or twice byhydroxyl, methoxy, chlorine or fluorine, or an oxoalkyl radical havingup to 6 carbon atoms, furthermore denoting a radical COR⁶, CN or SO₂ R⁷,R⁶ representing hydrogen, straight-chain or branched alkyl which has 1to 4 carbon atoms and is optionally substituted by 1 or 2 substituentsfrom the group comprising amino, alkoxycarbonyl having 1 to 3 carbonatoms in the alkyl moiety, carboxyl or alkoxy having 1 to 3 carbonatoms, or halogen such as chlorine, bromine or fluorine, or representingalkoxy having 1 to 4 carbon atoms, amino, alkylamino or dialkylaminohaving 1 to 5 carbon atoms in the alkyl moiety, and

R⁷ representing straight-chain or branched alkyl having 1 to 3 carbonatoms,

and their pharmaceutically utilisable hydrates, acid addition salts,alkali metal, alkaline earth metal and guanidinium salts, which havehigh antibacterial activity.

They are suitable as active compounds for human and veterinary medicine,veterinary medicine also including treatment of fish for the therapy orprevention of bacterial infections.

Preferred compounds of the formula (I') are those

in which

X¹ and X², which can be identical or different, represent chlorine orfluorine, but cannot both be fluorine, and

R³ and R⁴, together with the nitrogen atom to which they are bonded, canform a 5- or 6-membered heterocyclic ring which can contain in addition,as ring member, the atoms or groups --O--, --S--, --SO₂ --, N--R³ or##STR7## and which can optionally be substituted on the carbon atomsonce to twice by C₁ -C₃ -alkyl, cyclohexyl, phenyl which is optionallysubstituted once or twice by chlorine, fluorine, bromine, methyl,phenyl, hydroxyl, methoxy, benzyloxy, nitro or piperidino, 2-thienyl,hydroxyl, amino or methylamino,

R⁵ representing hydrogen, a branched or unbranched alkyl, alkenyl oralkinyl group having 1 to 4 carbon atoms, which can optionally besubstituted by one or two hydroxyl groups, or a phenacyl radical, anoxoalkyl radical having up to 5 carbon atoms, and representing a radicalCOR⁶,

R⁶ denoting hydrogen, straight-chain or branched alkyl having 1 to 3carbon atoms, alkoxy having 1 to 3 carbon atoms, amino, alkylamino ordialkylamino having 1 to 3 carbon atoms in the alkyl moiety.

Particularly preferred compounds of the formula (I') are those

in which

X¹ and X², which can be identical or different, represent chlorine orfluorine, but cannot both be fluorine, and

R³ and R⁴, together with the nitrogen atom to which they are bonded, canform a 5- or 6-membered heterocyclic ring which can contain in addition,as ring member, an oxygen atom or the groups N--R⁵ or ##STR8## and whichcan optionally be substituted on the carbon atoms once to twice by C₁-C₂ -alkyl, cyclohexyl, phenyl which is optionally substituted bychlorine, fluorine, methyl, phenyl, hydroxyl, methoxy, benzyloxy, nitroor piperidino, 2-thienyl or hydroxyl,

R⁵ representing hydrogen, a branched or unbranched alkyl group having 1to 3 carbon atoms which can optionally be substituted by one or twohydroxyl groups, or a phenacyl radical, an oxoalkyl radical having up to4 carbon atoms and a radical COR⁶,

R⁶ denoting hydrogen or alkyl having one or two carbon atoms.

It has also been found that the compounds of the formula (I') areobtained when the1-cyclopropyl-7-halogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidsof the formula (II') ##STR9## in which X¹ and X² have the abovementionedmeaning, and

X³ represents halogen, preferably chlorine or fluorine, are reacted withamines of the formula (III) ##STR10## in which R³ and R⁴ have theabovementioned meaning, where appropriate in the presence ofacid-binding agents (method A).

Compounds of the formula (I'), can also be obtained by reacting a7-(1-piperazinyl)-3-quinolone carboxylic acid of the formula (IV)##STR11## in which X¹ and X² have the abovementioned meaning, and thepiperazinyl radical can be substituted on the carbon atoms 1-3 times byC₁ -C₄ -alkyl, 2-thienyl or optionally substituted cyclohexyl or phenyl,with compounds of the formula (V)

    R.sup.5 X                                                  (V)

in which

R⁵ has the abovementioned meaning but cannot be hydrogen, and

X denotes fluorine, chlorine, bromine, iodine, hydroxyl, acyloxy,ethoxy, phenoxy or 4-nitrophenoxy,

where appropriate in the presence of acid-binding agents (method B).

Compounds of the formula (I'), are also obtained when7-(1-piperazinyl)-3-quinolonecarboxylic acid of the formula (IV), inwhich the piperazinyl radical can be substituted on the carbon atoms 1-3times by C₁ -C₄ -alkyl, 2-thienyl or optionally substituted cyclohexylor phenyl, is reacted with Michael acceptors of the formula (VI)

    B--CH═CH.sub.2                                         (VI)

in which

B represents CN, CO--R⁸ or COOR⁹,

R⁸ representing methyl or ethyl, and

R⁹ representing methyl, ethyl, n- or i-propyl,

(method C).

When, in the reaction by method A, 2-methylpiperazine and6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are used as starting materials, then the course of the reaction canbe represented by the equation below: ##STR12##

When, in the reaction by method B, ethyl iodide and6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid are used as starting materials, then the course of the reaction canbe represented by the equation below: ##STR13##

When, for example in the reaction of (IV) with (V) by method B,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid and formic acetic anhydride are used as starting compounds, thenthe course of the reaction can be represented by the equation below:##STR14##

When, for example by method C,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid and methyl vinyl ketone are used as starting compounds, then thecourse of the reaction can be represented by the equation below:##STR15##

The1-cyclopropyl-6,7,8-trihalogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylicacids of the formula (II') which can be used as starting materials bymethod A can be prepared in accordance with the following reactionscheme: ##STR16##

According to this, diethyl malonate (2) is acylated with the appropriatebenzoyl fluoride or chloride (1), in the presence of magnesium ethylate,to give the aroylmalonic ester (3) (Organicum, 3rd edition, 1964, page438).

By partial hydrolysis and decarboxylation of (3) in aqueous medium usingcatalytic amounts of sulphuric acid or p-toluenesulphonic acid, theethyl aroylacetates (4) are obtained in good yield, and these areconverted with triethyl orthoformate/acetic anhydride into ethyl2-(2,3,4,5-tetrahalogenobenzoyl)-3-ethoxyacrylates (5). The reaction of(5) with cyclopropylamine in a solvent such as, for example, methylenechloride, alcohol, chloroform, cyclohexane or toluene leads, in aslightly exothermic reaction, to the desired intermediate (6).

The cyclisation reaction (6)→(7) is carried out in a temperature rangeof about 60° to 300° C., preferably 80° to 180° C.

The diluents which can be used are dioxane, dimethyl sulphoxide,N-methylpyrrolidone, sulpholane, hexamethylphosphoric trisamide and,preferably, N,N-dimethylformamide.

Suitable acid-binding agents for this reaction step are potassiumtert.-butanolate, butyllithium, lithiumphenyl, phenyl magnesium bromide,sodium methylate, sodium hydride, sodium or potassium carbonate and,particularly preferably, potassium or sodium fluoride. It can beadvantageous to use an excess of 10 mol-% of base.

The ester hydrolysis of (7) carried out in the last step under basic oracid conditions leads to the1-cyclopropyl-6,7,8-trihalogeno-1,4-dihydro-4-oxo-3-quinolinecarboxylicacids (II).

The benzoyl halides (1) used as starting materials for this syntheticroute are prepared as follows: 3,5-dichloro-2,4-difluorobenzoyl fluoride(boiling point 97°/20 mbar; n_(D) ²⁰ =1.5148) and5-chloro-2,3,4-trifluorobenzoyl fluoride (boiling point 68°-70°/20 mbar;n_(D) ²⁰ = 1.4764) are obtained together by heating tetrachlorobenzoylchloride with potassium fluoride in sulpholane at elevated temperatures:##STR17##

The chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acidleads to 3-chloro-2,4,5-trifluorobenzoic acid which is reacted as thecrude product with thionyl chloride to give3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point 94°/18 mbar;n_(D) ²⁰ =1.5164): ##STR18##

The amines (III) used as starting materials are known or can be obtainedby processes known from the literature [U.S. Pat. No. 4,166,180, J. Med.Chem. 26, 1116 (1983). From the 2-arylpiperazines, the corresponding2-cyclohexylpiperazines are obtained by catalytic hydrogenation; forexample: 2-cyclohexylpiperazine (waxlike, melting point 71°-73° C.).Examples which may be mentioned are: morpholine, piperidine,thiomorpholine, pyrrolidine, piperazine, N-methylpiperazine,N-ethylpiperazine, N-(2-hydroxyethyl)piperazine, N-formylpiperazine,2-methylpiperazine, 1,2-dimethylpiperazine, cis- andtrans-2,5-dimethylpiperazine, cis- and trans-2,6-dimethylpiperazine,2-ethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine,2-isobutylpiperazine, 2-piperazinone, 1-methyl-2-piperazinone,1-ethyl-2-piperazinone, 2-cyclohexylpiperazine piperazine,2-phenylpiperazine, 2-(4-chlorophenyl)piperazine,2-(4-fluorophenyl)piperazine, 2-(4-bromophenyl)piperazine,2-(4-methylphenyl)piperazine, 2-(4-biphenylyl)-piperazine.2-(4-methoxyphenyl)piperazine, 2-(4-benzyloxyphenyl)piperazine,2-(4-hydroxyphenyl)piperazine, 2-(4-nitrophenyl)piperazine,2-(3-nitrophenyl)piperazine, 2-(4-piperidinophenyl)piperazine,2-(3,4-dimethoxyphenyl)piperazine, 2-(3,4,5-trimethoxyphenyl)piperazine,2-(3,4-dimethoxy-6-methyl)piperazine, 2-(2-thienyl)piperazine and3-aminopyrrolidine.

The compounds of the formula (V) which are used as starting materialsare known. Examples which may be mentioned are: methyl iodide, methylbromide, ethyl iodide, ethyl bromide, ethyl chloride, 2-hydroxyethylchloride, 3-hydroxypropyl chloride, 4-hydroxybutyl chloride, n-propylbromide, i-propyl iodide, n-butyl bromide, i-butyl bromide, sec.-butylchloride, n-pentyl chloride, 3-methylbutyl chloride and n-hexyl bromide,formic acetic anhydride, acetic anhydride, propionic anhydride, acetylchloride, chloroacetyl chloride, onic anhydride, acetyl chloride,chloroacetyl chloride, dichloroacetyl chloride, bromoacetyl bromide,butyryl chloride, 4-chlorobutyryl chloride, isobutyryl chloride,4-nitrophenyl ester of N-(tert.-butoxycarbonyl)-glycine, 4-nitrophenylester of N-(tert.-butoxycarbonyl)-L-alanine, 4-nitrophenyl ester ofN-(tert.-butoxycarbonyl)-L-leucine, 4-nitrophenyl ester ofN-(tert.-butoxycarbonyl)-L-valine, 3-methoxypropionyl chloride, methylchlorocarbonate, ethyl chlorocarbonate, n-butyl chlorocarbonate, diethylcarbonate, cyanogen chloride, diphenyl carbonate, cyanogen bromide,dimethylcarbamoyl chloride, methanesulphonyl chloride, ethanesulphonylchloride, propane-1-sulphonyl chloride and formic acid.

The compounds of the formula (VII) which can be used according to theinvention are known. Examples which may be mentioned are: acrylonitrile,methyl vinyl ketone, methyl acrylate and ethyl acrylate.

The reaction of (II) with (III) by method A is preferably carried out ina diluent such as dimethyl sulphoxide, N,N-dimethylformamide,hexamethylphosphoric trisamide, sulpholane, water, an alcohol, such asmethanol, ethanol, n-propanol, isopropanol or glycol monomethyl ether,or pyridine. It is equally possible to use mixtures of these solvents.

All customary inorganic and organic acid-binding agents can be used asthe acid-binding agent. These preferably include the alkali metalhydroxides, alkali metal carbonates, organic amides and amidines. Thefollowing may be specifically mentioned as being particularly suitable:triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a relatively wide range.In general, the process is carried out between about 20° and 200° C.,preferably between 80° and 180° C.

The reaction can be carried out under atmospheric pressure as well asunder elevated pressure. In general, it is carried out under pressuresbetween about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention, 1 to 15 moles,preferably 1 to 6 moles, of the amine (III) are used for 1 mole ofcarboxylic acid (II).

The reaction of (IV) with (V) is preferably carried out in a diluentsuch as dimethyl sulphoxide, dioxane, N,N-dimethylformamide,hexamethylphosphoric trisamide, sulpholane, water, an alcohol, such asmethanol, ethanol, n-propanol, isopropanol or glycol monomethyl ether,or pyridine. It is equally possible to use mixtures of these diluents.

All customary inorganic and organic acid-binding agents can be used asthe acid-binding agent. These preferably include the alkali metalhydroxides, alkali metal carbonates, organic amines and amides. Thefollowing may be specifically mentioned as being particularly suitable:triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The reaction temperatures can be varied within a relatively wide range.In general, the process is carried out between about 20° and about 180°C., preferably between 40° and 110° C.

The reaction can be carried out under atmospheric pressure as well asunder elevated pressure. In general, it is carried out under pressuresbetween about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention by method B, 1to 4 moles, preferably 1 to 1.5 mole, of the compound (V) is used for 1mole of the compound (IV).

The reaction of (IV) with (VI) (method C) is preferably carried out in adiluent such as dioxane, dimethyl sulphoxide, N,N-dimethylformamide,methanol, ethanol, isopropanol, n-propanol or glycol monomethyl ether orin mixtures of these diluents.

The reaction temperatures can be varied within a relatively wide range.In general, the process is carried out between about 20° C. and about150° C., preferably between 50° C. and 100° C.

The reaction can be carried out under atmospheric pressure as well asunder elevated pressure. In general, it is carried out under pressuresbetween about 1 and about 100 bar, preferably between 1 and 10 bar.

When carrying out the process according to the invention by method C, 1to 5 moles, preferably 1 to 2 moles, of the compound (VI) are used for 1mole of the compound (IV).

Apart from the compounds listed in the examples, the following may bespecifically mentioned as active compounds obtainable from the compoundsof the invention: 6-chloro-7-[3-(4-chlorophenyl)-1-piperazinyl]1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,6-chloro-1-cyclopropyl-8-fluoro-7-[3-(4-fluorophenyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,7-[3-(4-bromophenyl)-1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methylphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,7-[3-(4-biphenyl)1-piperazinyl]-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-methoxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[3-(4-hyroxyphenyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-nitrophenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(4-piperidino-phenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4-dimethoxy-phenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3,4,5-trimethyoxy-phenyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylicacid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperidino-3-quinolinecarboxylicacid,7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6,8-dichloro-1-cyclopropyl-1,4-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,7-(4-acetyl-1-piperazinyl)-6,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,7-(4-acetyl-1-piperazinyl)-6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-morpholino-3-quinolinecarboxylicacid,6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-thiomorpholino-3-quinolinecarboxylicacid and8-chloro-1-cyclopropyl-7-(4-ethyl-3-oxo-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

The examples which follow shall illustrate end products obtainable fromcompounds which are subject matter of the present invention.

EXAMPLE A

6-Chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid ##STR19##

15.7 g (0.65 mole) of magnesium turnings are stirred in 40 ml of ethanoland 2 ml of tetrachloromethane and, after the reaction has started, 103g (0.64 mole) of diethyl malonate in 80 ml of ethanol and 250 ml oftoluene are added dropwise at 50°-60°. The mixture is stirred at thistemperature for 1 hour, cooled to -5° to -10°, a solution of 138 g (0.65mole) of 5-chloro-2,3,4-trifluoro-benzoyl fluoride in 63 ml of tolueneis added dropwise, and the mixture is stirred further at 0° for 1 hourand allowed to stand overnight at room temperature. It is then heated at40°-50° for 2 hours, cooled, and 250 ml of ice-water and 38.5 ml ofconcentrated sulphuric acid are added. The organic phase is separatedoff, the aqueous phase is extracted with 2×150 ml of toluene, and thecombined organic phases are washed with saturated sodium chloridesolution, dried with sodium sulphate and concentrated.

200 ml of water are added to the residue (it is advantageous to add 0.4g of 4-toluenesulphonic acid at this point) and the mixture is heatedunder reflux for 5 hours for the deethoxycarbonylation. The mixture isextracted with 3×200 ml of dichloromethane, and the extracts are washedwith saturated sodium chloride solution, dried with sodium sulphate,concentrated and distilled under high vacuum. 103 g (56.5%) of ethyl(5-chloro-2,3,4-trifluorobenzoyl)-acetate with a boiling point of110°/0.9 Torr are obtained.

103 g (0.37 mole) of the ester obtained and 83 g (0.56 mole) of triethylorthoformate are heated with 95 g of acetic anhydride at 150°-160° for 2hours and then concentrated at 120°-130° under atmospheric pressure andthereafter under high vacuum. 115 g (92% of theory) of ethyl2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyacrylate are obtained as anoil.

14.8 g (0.26 mole) of cyclopropylamine are added dropwise to 84.1 g(0.25 mole) of this compound in 170 ml of ethanol, cooling in ice, andthe mixture is stirred at room temperature for 2 hours. It is thenstirred with 170 ml of water, cooled in ice, and the precipitate whichhas separated out is filtered off with suction, washed with water and alittle methanol and dried. 47 g (54%) of ethyl2-(5-chloro-2,3,4-trifluorbenzoyl)-3-cyclopropylaminoacrylate of meltingpoint 71°-73° are obtained. The product is a cis/trans mixture accordingto the ¹ H NMR spectrum.

47 g (0.14 mole) of this compound in 230 ml of dimethylformamide areheated with 9.7 g (0.23 mole) of sodium floride at 160°-170° for 2hours. The reaction mixture is poured into 400 ml of ice-water, and theprecipitate is filtered off with suction, washed with water and dried.44 g (99%) of ethyl6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 169°-172° are isolated.

33 ml of concentrated sulphuric acid are added to 44 g (0.13 mole) ofthe quinolonecarboxylic ester in 300 ml of glacial acetic acid and 179ml of water and the reaction mixture is heated at 150° C. for 2 hours.It is stirred into 400 ml of ice-water, and the precipitate is filteredoff with suction, washed with water and dried. 37 g (95% of theory) of6-chloro-1-cyclopropyl-7,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are isolated with a melting point of 200°-204°.

EXAMPLE B

8-Chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid. ##STR20##

3-Chloro-2,4,5-trifluorobenzoyl chloride is reacted in analogy toExample A, the following steps being passed through: ethyl(3-chloro-2,4,5-trifluorobenzoyl)acetate as the enol (yield: 42%,melting point 72-75), ethyl2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (crude yield: 95%oil), ethyl2-(3-chloro-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate (yield:67%, melting point 78°-80°), ethyl8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(yield: 85%, melting point 154°-157°),8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (yield: 97.6%, melting point 189°-192°).

EXAMPLE C

6,8-Dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid ##STR21##

3,5-Dichloro-2,4-difluorobenzoyl fluoride is reacted in analogy toExample A, the following steps being passed through: ethyl(3,5-dichloro-2,4-difluorobenzoyl)acetate (yield: 43%, melting point133°/2.5 Torr), ethyl2-(3,5-dichloro-2,4-difluorobenzoyl)-3-ethoxyacrylate (crude yield: 95%oil), ethyl2-(3,5-dichloro-2,4-difluorobenzoyl)-3-cyclopropylaminoacrylate (yield:96%, melting point 71°-74°), ethyl6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate(yield: 97%, melting point 215°-217° with decomposition),6,8-dichloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (yield: 93%, melting point 204°-206°).

EXAMPLE 1 ##STR22##

12 g (40 mmol) of the product from Example A in 100 ml of pyridine areheated with 17.2 g (0.2 mole) of piperazine under reflux for 5 hours.The mixture is concentrated in vacuo, the residue is stirred with 120 mlof water and the pH is adjusted to 5 with 2N hydrochloric acid. Theprecipitate is filtered off with suction, washed with water andmethanol, boiled in 80 ml of methanol and dried. 12.3 g (84% of theory)6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid of melting point 295°-298° (with decomposition) are obtained.

The following6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacids substituted in the 7-position are obtained in analogy to Example1:

    ______________________________________                                         ##STR23##                                                                     ##STR24##                                                                             ##STR25##                                                                                         ##STR26##                                        ______________________________________                                                 ##STR27##          258-282° (decomposition)                   3                                                                                      ##STR28##          191-195° (decomposition)                   4                                                                                      ##STR29##          above˜274° (decomposition)           5                                                                                      ##STR30##          255-261° (decomposition)                   6                                                                                      ##STR31##          >320° (decomposition)                      7                                                                                      ##STR32##          276-280° (decomposition)                   8                                                                                      ##STR33##          above˜190° (decomposition)           9                                                                                      ##STR34##          154-158                                           ______________________________________                                    

EXAMPLE 10 ##STR35##

1.83 g (5 mmol) of the product from Example 1 in 20 ml ofdimethylformamide are heated with 1.6 g of ethyl iodide and 1 g oftriethylamine at 80° for 3 hours. The reaction mixture is concentratedin vacuo, and the residue is stirred with 20 ml of water andrecrystallised from methanol. 0.4 g (15% of theory) of6-chloro-1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 237°-242° (with decomposition) is obtained.

EXAMPLE 11 ##STR36##

3.65 g (0.01 mmol) of the product from Example 1 are suspended in 150 mlof ethanol and 30 ml of water, the suspension is adjusted to pH 4.6 withacetic acid, and then, at room temperature, 3.4 g (0.02 mol) of2,3-cyclo-hexylideneglyceraldehyde and, in portions, 950 mg of sodiumcyanoborohydride are added. The mixture is stirred at room temperatureovernight, the pH is adjusted to 8 with sodium bicarbonate, extractionwith dichloromethane is carried out, and the extract is concentrated. 3ml of concentrated hydrochloric acid are added to the residue in 25 mlof ethanol and 25 ml of water, and the mixture is heated under refluxfor 6 hours. It is concentrated, the residue is dissolved in water, thesolution is extracted with dichloromethane, concentration is againcarried out, and the residue is stirred with ethanol and dried. 1.3 g of6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-[4-(2,3-dihydroxypropyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 263°-266° (with decomposition) isobtained.

EXAMPLE 12 ##STR37##

1.83 g (5 mmol) of the product from Example 1 and 1.95 g(28 mmol) ofmethyl vinyl ketone in 25 ml of ethanol are heated under reflux for 6hours, and the precipitate is filtered off with suction andrecrystallised from glycol monomethy ether. 1 g (46% of theory) of6-chloro-1-cyclopropyl-8fluoro-1,4-dihydro-4-oxo-7-[4-(3-oxobutyl)-1-piperazinyl]-3-quinolinecarboxylicacid of melting point 187°-190° (with decomposition) is obtained.

EXAMPLE 13 ##STR38##

1.83 g (5 mmol) of the product from Example 1 in 25 ml of ethanol areheated with 1.95 g (20 mmol) of chloroacetone under reflux for 6 hours.The suspension is cooled, and the precipitate is filtered off withsuction, thoroughly washed with ethanol and dried in vacuo, 1 g (44% oftheory) of6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxopropyl)-1-piperazinyl]-3quinolinecarboxylicacid hydrochloride of melting point ˜320° C. with decomposition) beingobtained.

EXAMPLE 14 ##STR39##

3.66 g (0.01 mole) of the product from Example 1 in 50 ml ofdimethylformamide are heated with 2.2 g of ω-chloroacetophenone and 2.2g of triethylamine at 60° for 10 hours. The reaction mixture isconcentrated in vacuo, the residue is stirred with 30 ml of water, andthe precipitate is filtered off with suction, washed with water andrecrystallised from acetone. 1.2 g (25% of theory) of6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxo-2-phenylethyl)-1-piperazinyl]-3-quinolinecarboxylicacid of melting point 175°-179° (with decomposition) is obtained.

EXAMPLE 15 ##STR40##

1.5 g (4 mmol) of the product from Example 1 are dissolved in a mixtureof 10 ml of dioxane and 170 mg of sodium hydroxide in 2.5 ml of waterand then, simultaneously, a solution of 0.7 g of formic acetic anhydridein 5 ml of dioxane and a solution of 340 mg of sodium hydroxide in 5 mlof water are added. The mixture is stirred at room temperature for 2hours, diluted with 30 ml of water, and the precipitate is filtered offwith suction, washed with water and methanol and recrystallised fromglycol monomethyl ether. 0.6 g (38%) of6-chloro-1-cyclopropyl-8-fluoro-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 277°-278° (with decomposition) is obtained.

EXAMPLE 16 ##STR41##

When the product from Example 2 is reacted in analogy to Example 15,then6-chloro-1-cyclopropyl-8-fluoro-7-(4-formyl-3-methyl-1piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 280°-282° (with decomposition) is obtained.

EXAMPLE 17 ##STR42##

3 g (10 mmol) of the product from Example A in 35 ml of dimethylsulphoxide are heated at 140° with 1.2 g (10 mmol) of2,6-dimethylmorpholine and 2.2 g (20 mmol) of diazabicyclo[2.2.2]octanefor 5 hours. The mixture is concentrated under high vacuum, stirred with30 ml of water, the pH is adjusted to 6 with 2N hydrochloric acid, andthe precipitate is filtered off with suction and recrystallized fromglycol monomethyl ether. 1.6 g (41% of theory) of6-chloro-1cyclopropyl-8-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-moropholinyl)-4-oxo-3-quinolinecarboxylicacid of melting point 258°-261° (with decomposition) is obtained.

EXAMPLE 18 ##STR43##

When the product from Example A is reacted with 4-hydroxypiperidine inanalogy to Example 17, then6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxo-3-quinolinecarboxylicacid of melting point 226°-231° (with decomposition) is obtained.

EXAMPLE 19 ##STR44##

3 g (0.01 mole) of the product from Example B in 25 ml of pyridine areheated with 4 g (0.04 mole) of 1-methylpiperazine under reflux for 5hours. The mixture is concentrated in vacuo, 20 ml of water are added,the pH is adjusted to 5 with 2N hydrochloric acid, and the precipitatewhich has separated out is recrystallised from methanol. 0.6 g (16% oftheory) of8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid of melting point 293°-297° (with decomposition) is obtained.

EXAMPLE 20 ##STR45##

In analogy to Example 19, with 2-methylpiperazine,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid of melting point 318°-325° (with decomposition) is obtained.

EXAMPLE 21 ##STR46##

In analogy to Example 19, the product from Example 8 is reacted withpiperazine under reflux for 1.5 hours, and the reaction mixture istreated with hydrochloric acid,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-3-quinolinecarboxylicacid hydrochloride with a decomposition point above 330° being obtained.

EXAMPLE 22 ##STR47##

When the product from Example C is reacted with 2-methylpiperazine inanalogy to Example 19, then6,8-dichloro-1-cyclopropyl-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid of melting point 288°-291° (with decomposition) is obtained.

EXAMPLE 23 ##STR48##

3.2 g (0.01 mole) of the product from Example C are heated with 4 g(0.04 mole) of 1-methylpiperazine at 80° for 3 days, the reactionmixture is concentrated in vacuo, and the residue is taken up in alittle water and the pH is adjusted to 7 with 2N hydrochloric acid.Crystallisation takes place on standing in ice. The precipitate wasfiltered off with suction and recrystallised from water with theaddition of a little hydrochloric acid. 0.6 g6,8-dichloro-1-cyclopropyl-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid of melting point>300° is obtained.

EXAMPLE 24 ##STR49##

3 g (10 mmol) of the product from Example 1 in 25 ml of dimethylsulphoxide are heated with 1.8 g (18 mmol) of 2-piperazinone and 2.2 g(20 mmol) of diazabicyclo[2.2.2]octane at 130° for 2 hours. Thesuspension is adjusted to pH 5 with 2N hydrochloric acid, 25 ml of waterare added, and the precipitate is filtered off with suction, extractedby boiling with 20 ml of methanol and dried. 1.5 g (39% of theory) of6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylicacid of melting point 288°-291° (with decomposition) is obtained.

Examples following are examples of compounds according to the presentinvention:

EXAMPLE 25

2,4,5-Trifluorobenzoyl fluoride

By treating 2,4-dichloro-5-fluorobenzoylchloride (b.p. 113/14 mbar,n_(D) ²⁰ : 1.5722) with a 4-fold excess of anhydrous HF at 120° in anautoclave for 3 hours with the elimination of hydrogen chloride,2,4-dichloro-5-fluorobenzoyl fluoride with a boiling point of 98° C./15mbar, n_(D) ²⁰ : 1.5355, is prepared.

878 g of 2,4-dichloro-5-fluorobenzoyl fluoride are reacted, in 2,350 mlof tetramethylene sulphone in a three-necked flask with stirrer,thermometer and a distillation column, with 1,142 g of anhydrous KF at200° C. for 3.5 hours. During this, distillate is continuously removedthrough the distillation column, initially at 750 mbar, and towards theend at about 80 mbar. The crude distillate is subjected to fractionalredistillation. 486 g (65.5% of theory) of 2,4,5-trifluorobenzoylfluoride, of boiling point 52°-3°/20 mbar, n_(D) ²⁰ : 1.4530, areobtained.

After hydrolysis of 161 g of 2,4,5-trifluorobenzoyl fluoride with asolution of 100 g of sodium hydroxide in 1 l of water at 40° (exothermicup to 70°), diluting the mixture with 1 l of water, acidifying thediluted mixture with hydrochloric acid filtering the acidified mixtureand drying the product 2,4,5-trifluorobenzoic acid with a melting pointof 95° C. is obtained in an almost quantitative yield.

EXAMPLE 26

Fluorination of 2,3,4,5-tetrachlorobenzoyl chloride

2,749 g of 2,3,4,5-tetrachlorobenzoyl fluoride, of melting point 52°-53°C., are obtained from 2,994 g of 2,3,4,5-tetrachlorobenzoyl chloride, ofboiling point 118° C./0.5 mbar, melting point 38° C., after fluorinationwith 1.6 l of anhydrous hydrofluoric acid in 2.0 l of methylene chlorideat 60° C. in an autoclave (5 hours), and after distillation of the HFand the solvent.

This quantity is heated together with 2,914 g of anhydrous KF in 7,250ml of tetramethylene sulphone in a three-necked flask, and initiallyabout 500 ml of the solvent is distilled out again to remove anyresidual water. The reaction mixture is then heated at 240° C., withvigorous stirring, for about 4.5 hours. During this, the initialpressure of 800 mbar is reduced continuously to 500 mbar. At the sametime, the mixture of fluorination products is removed as the distillatethrough the fractionating column. The total obtained is 1,840 g. Thefollowing are obtained from this by fractional redistillation:

206 g of 2,3,4,5-tetrafluorobenzoyl fluoride, boiling point: 45°-7°C./20 mbar, n_(D) ²⁰ : 1.4372;

954 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride, boiling point:68°-70° C./20 mbar, n_(D) ²⁰ : 1.4764;

330 g of 3,5-dichloro-2,4-difluorobenzoyl fluoride, boiling point: 97°C./20 mbar, n_(D) ²⁰ : 1.5148.

64 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride are heated with 13 g ofSiCl₄ in the presence of 0.1 g of AlCl₃. The reaction starts at about35° C. and is completed at a temperature of up to about 100° C., andthen the residue is worked up by distillation. The following isobtained:

62 g of 5-chloro-2,3,4-trifluorobenzoyl chloride, boiling point: 88°C./14 mbar, n_(D) ²⁰ : 1.5146.

3,5-Dichloro-2,4-difluorobenzoyl chloride is also obtainedcorrespondingly, as a liquid of boiling point 113°-4° C./15 mbar, n_(D)²⁰ : 1.5512.

When 5-chloro-2,3,4-trifluorobenzoyl fluoride is briefly treated withaqueous sodium hydroxide solution then, after acidification and drying,crystals of 5-chloro-2,3,4-trifluorobenzoic acid are obtained, meltingpoint: 123°-4° C.

3,5-Dichloro-2,4-difluorobenzoic acid is obtained correspondingly,melting point: 179° C.

EXAMPLE 27

5-Chloro-2,3,4-trifluorobenzyl alcohol

62 g of NaBH₄ are initially introduced into 320 ml of dioxane. Asolution of 319 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride in 640 mlof dioxane is run into this, at the reflux temperature, over the courseof 6 hours. After boiling under reflux for a further hour, the mixtureis poured onto ice, the pH is adjusted to 1 with dilute hydrochloricacid, and the organic phase is extracted with methylene chloride andthen distilled: 261 g of 2,3,4-trifluoro-5-chlorobenzyl alcohol ofboiling point 109° C./12 mbar are obtained.

3,5-Dichloro-2,4-difluorobenzyl alcohol is obtained correspondingly, ascrystals of boiling point 134° C./13 mbar, melting point: 55° C., from3,5-dichloro-2,4-difluorobenzoyl fluoride.

EXAMPLE 28

3-Chloro-2,4,5-trifluorobenzoyl fluoride

150 g of 2,4,5-trifluorobenzoic acid are dissolved in 150 ml ofchlorosulfonic acid and, after addition of 3 g of iodine, chlorinationis carried out with gaseous chlorine at 50° to 60° C. Chlorination iscontinued until about 35 to 50% of the starting material has beenconverted, and then the mixture is cautiously decomposed on ice.

The mixture of nuclear halogenated acids is filtered off with suctionand dried (purification of a sample by repeated recrystallization givesa melting point of 114°-5° C. for 3-chloro-2,4,5-trifluorobenzoic acid).

The crude mixture is converted into the mixture of acid chlorides usingexcess thionyl chloride in the presence of a few drops ofdimethylformamide. 3-Chloro-2,4,5-trifluorobenzoyl chloride is isolatedby precision distillation of a sample, boiling point 94° C./18 mbar,n_(D) ²⁰ :1.5164.

100 ml of anhydrous HF are added to the remainder in a stainless steelautoclave at about -5° C. and, after the evolution of HCl has subsided,the mixture is briefly heated to 60° C. to complete the reaction andthen worked up by distillation. 38 g of 3-chloro-2,4,5-trifluorobenzoylfluoride of boiling point 65° C./18 mbar, n_(D) ²⁰ :1.4760 are isolated.

3-Chloro-2,4,5-trifluorobenzyl alcohol is obtained by reduction of theacid fluoride with NaBH₄ : boiling point 109° C./14 mbar, melting point32° C.

39 g of 3-chloro-2,4,5-trifluorobenzyl alcohol are oxidised in 92 ml ofacetone with a solution of 20 g of Na₂ Cr₂ O₇ in 81 ml of water and 14ml of concentrated sulphuric acid for 2 hours at 20° to 25° C., theorganic phase is washed with aqueous sodium carbonate solution and driedwith sodium sulphate. After evaporating off the solvent and afterdistillation 2,4,5-trifluoro-3-chlorobenzaldehyde, b.p. 72° C./12 mbar,n_(D) ²⁰ : 1.5055, which crystallises slowly and has a melting point of31°-32° C., is obtained.

EXAMPLE 29

Fluorination of 2,3,4,5-tetrachlorobenzonitrile

2,3,4,5-Tetrachlorobenzonitrile of melting point: 123°-5° C. (preparedfrom 2,3,4,5-tetrachlorobenzoyl chloride, melting point: 30° C., via2,3,4,5-tetrachlorobenzamide, melting point: 206° ) are fluorinated withKF in tetramethylene sulphone. The following are isolated by fractionaldistillation of the fluorination mixture:

2,3,4,5-tetrafluorobenzonitrile, boiling point 59° C./15 mbar, n_(D) ²⁰: 1.4562;

5-chloro-2,3,4-trifluorobenzonitrile, boiling point 78° C./14 mbar,n_(D) ²⁰ 1.4960; and

3,5-dichloro-2,4-difluorobenzonitrile, boiling point 113° C./19 mbar,melting point: 39°-40° C.

EXAMPLE 30

3,5-Dichloro-2,4-difluorobenzamide

620 ml of concentrated aqueous ammonia solution and 600 ml of water areinitially introduced, 458 g (2 moles) of3,5-dichloro-2,4-difluorobenzoyl fluoride are added dropwise at 40°-50°,and then the mixture is stirred at 50° for 30 minutes. The precipitateis filtered off with suction, washed with water and dried. 408 g (90% oftheory) of 3,5-dichloro-2,4-difluorobenzamide of melting point 163°-164°are obtained.

The following are obtained analogously:

5-chloro-2,3,4-trifluorobenzamide, melting point: 135°-137°,

3-chloro-2,4,5-trifluorobenzamide, melting point: 125°,

2,4,5-trifluorobenzamide, melting point: 145°-147°, and

2,3,4,5-trichlorobenzamide, melting point: 206°.

EXAMPLE 31

3,5-Dichloro-2,4-difluorobenzyl chloride

354 ml of thionyl chloride and 1 drop of dimethylformamide are initiallyintroduced at room temperature, and 375 g (1.76 mol) of3,5-dichloro-2,4-difluorobenzyl alcohol are added dropwise. The mixtureis heated under reflux until evolution of gas has finished. The excessthionyl chloride is removed by distillation, and the residue isdistilled in vacuo. 386 g (95% of theory) of3,5-dichloro-2,4-difluorobenzyl chloride of boiling point 107°/12 mbar,n_(D) ²⁰ : 1.5368, are obtained. The following are obtained analogously:

5-chloro-2,3,4-trifluorobenzyl chloride, boiling point 78°/13 mbar;n_(D) ²⁰ : 1.4972, and

3-chloro-2,4,5-trifluorobenzyl chloride, boiling point 80°/16 mbar;n_(D) ²⁰ : 1.4966.

EXAMPLE 32

Chlorination of 5-chloro-2,3,4-trifluorobenzyl chloride

187 g (0.87 mol) of 5-chloro-2,3,4-trifluorobenzyl chloride areinitially introduced and are chlorinated with less than thestoichiometric amount of chloride, at 100°-105° C. with UV irradiation.According to assay by gas chromatography, the crude mixture contains 66%5-chloro-2,3,4-trifluorobenzal chloride and 32%5-chloro-2,3,4-trifluorobenzotrichloride. The following are obtainedafter fractional distillation:

94 g (43% of theory) of 5-chloro-2,3,4-trifluorobenzal chloride, boilingpoint 88°/12 mbar, n_(D) ²⁰ 1.5082;

33 g (13% of theory) of 5-chloro-2,3,4-trifluorobenzotrichloride,boiling point 104°/12 mbar, n_(D) ²⁰ : 1.5235.

The following are obtained analogously:

3,5-dichloro-2,4-difluorobenzal chloride, boiling point 114°/14 mbar,n_(D) ²⁰ : 1.5443,

3,5-dichloro-2,4-difluorobenzotrichloride, boiling point 128°/14 mbar,melting point 43°.

EXAMPLE 33

5-Chloro-2,3,4-trifluorobenzaldehyde

72 g (0.29 mol) of 5-chloro-2,3,4-trifluorobenzal chloride are added to220 g of 95% strength sulphuric acid at 40°, and stirring is continuedat 40° until evolution of gas has finished.

The residue is poured onto ice, extracted with methylene chloride, andthe organic phase is dried with sodium sulphate, concentrated anddistilled. 18 g (32% of theory) of 5-chloro-2,3,4-trifluorobenzaldehydeof boiling point 73°/15 mbar, n_(D) ²⁰ : 1.5020 are obtained.

The following is obtained analogously:

3,5-dichloro-2,4-difluorobenzaldehyde, boiling point 98°/14 mbar,melting point 32°.

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

Example of a tablet containing end products obtainable by using thecompounds of the invention

    ______________________________________                                        Each tablet contains:                                                         Compound of Example 1    583.0  mg                                            Microcrystalline cellulose                                                                             55.0   mg                                            Maize starch             72.0   mg                                            Poly(1-vinyl-2-pyrrolidone)                                                                            30.0   mg                                            insoluble                                                                     Highly disperse silica   5.0    mg                                            Magnesium stearate       5.0    mg                                                                     750.0  mg                                            The lacquer coating contains:                                                 Poly(0-hydroxypropyl 0-methyl)-                                                                        6.0    mg                                            cellulose 15 cp                                                               Macrogol 4000 rec. INN   2.0    mg                                            (polyethylene glycol DAB)                                                     Titanium (IV) oxide      2.0    mg                                                                     10.0   mg                                            ______________________________________                                    

The end products have very low toxicity and exhibit a broadantibacterial spectrum towards Gram-positive and Gram-negativeorganisms, especially towards enterobacteriaceae; especially includingthose which are resistant to various antibiotics, such as, for example,penicillins, cephalosporins, aminoglycosides, sulphonamides andtetracyclines.

These valuable properties make it possible to use them aschemotherapeutic active compounds in medicine and as substances topreserve inorganic and organic materials, especially organic materialsof all types, for example polymers, lubricants, dyes, fibres, leather,paper and wood, and foodstuffs and water.

The end products are active against a very broad spectrum ofmicroorganisms. Using them, it is possible to control Gram-negative andGram-positive bacteria and bacteroid microorganisms and to prevent,ameliorate and/or heal illnesses caused by these pathogens.

The end products are particularly active against bacteria and bacteroidmicroorganisms. Thus, they are especially suitable for the prophylaxisand chemotherapy of local and systemic infections caused by thesepathogens in human and veterinary medicine.

For example, local and/or systemic illnesses which are caused by thefollowing pathogens or by mixtures of the following pathogens can betreated and/or prevented: micrococcaceae, such as Staphylococci, forexample Staphylococcus aureus, Staph. Epidermidis,(Staph.=Staphylococcus); Lactobacteriaceae, such as Streptococci, forexample Streptococcus pyogenes,α- and β-haemolytic Streptococci,non-γ-haemolytic Streptococci, Enterococci and Diplococcus pneumoniae(Pneumococci) (Str.=Streptococcus); Enterobacteriaceae, such asEscherichiae bacteria of the Escherichia group, for example Escherichiacoli, Enterobacter bacteria, for example E. aerogenes and E. cloacae(E.=Enterobacter), Klebsiella bacteria, for example K. pneumoniae(K.=Klebsiella), Serratia, for example Serratia marcescens, Proteaebacteria of the Proteus group: Proteus, for example Pr. vulgaris, Pr.morganii, Pr. rettgeri and Pr. mirabilis (Pr.=Proteus);Pseudomonadaceae, such as Pseudomonas bacteria, for example Ps.aeruginosa (Ps.=Pseudomonas); Bacteroidaceae, such as Bacteroidesbacteria, for example Bacteroides fragilis Mycoplasma, for exampleMycoplasma pneumoniae, also Mycobacteria, for example Mycobacteriumtuberculosis, Mycobacterium Leprae and atypical Mycobacteria.

The above list of pathogens is purely illustrative and is in no way tobe interpreted as restrictive. The following may be mentioned asexamples of illnesses which can be prevented, ameliorated and/or healedby the end products: otitis; pharyngitis; pneumonia; peritonitis;pyelonephritis; cystitis; endocarditis, systemic infections; bronchitis;arthritis; local infections and septic illnesses.

The end products can be used as pharmaceutical preparations which inaddition to non-toxic, inert pharmaceutically vehicles contain one ormore compounds or which consist of one or more active compounds.

The end products can be used as pharmaceutical preparations in dosageunits. This means that the preparation are in the form of individualparts, for example tablets, coated tablets, capsules, pills,suppositories and ampoules, of which the content of active compoundcorresponds to a fraction or a multiple of an individual dose. Thedosage units can contain, for example, 1, 2, 3 or 4 individual doses or1/2, 1/3 or 1/4 of an individual dose. An individual dose preferablycontains the amount of active compound which is given in oneadministration and which usually corresponds to a whole, a half, or athird or a quarter of a daily dose.

By non-toxic, inert pharmaceutically suitable vehicles there are to beunderstood solid, semi-solid or liquid diluents, fillers and formulationauxiliaries of all kinds.

Tablets, coated tablets, capsules, pills, granules, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, creams,lotions, powders and sprays may be mentioned as preferred pharmaceuticalpreparations.

Tablets, coated tablets, capsules, pills and granules can contain theactive compound or compounds along-side the customary vehicles such as(a) fillers and extenders, for example starches, lactose, sucrose,glucose, mannitol and silica, (b) binders, for examplecarboxymethyl-cellulose, alginates, gelatin and polyvinylpyrrolidone,(c) humectants, for example glycerol, (d) disintegrating agents, forexample agar-agar, calcium carbonate and sodium carbonate, (e) solutionretarders, for example paraffin, and (f) absorption accelerators, forexample quaternary ammonium compounds, (g) wetting agents, for examplecetyl alcohol or glycerol monostearate, (h) adsorbents, for examplekaolin and bentonite and (i) lubricants, for example talc, calcium andmagnesium stearate and solid polyethylene glycols, or mixtures of thesesubstances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can beprovided with the customary coatings and shells, optionally containingopacifying agents, and can also be of such composition that they releasethe active compound or compounds only, or preferentially, in a certainpart of the intestinal tract, optionally in a delayed manner, examplesof embedding compositions which can be used being polymeric substancesand waxes.

The active end products, optionally together with one or more of theabovementioned vehicles, can also be in a microencapsulated form.

Suppositories can contain, in addition to the active end products, thecustomary water-soluble or water-insoluble vehicles, for examplepolyethylene glycols, fats, for example cacao fat, and higher esters(for example C₁₄ -alcohol with C₁₆ -fatty acids), or mixtures of thesesubstances.

Ointments, pastes, creams and gels can contain the customary vehicles inaddition to the active end products, for example animal and vegetablefats, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silica, talc and zinc oxideor mixtures of these substances.

Powders and sprays can contain the customary vehicles in addition to theactive end products, for example lactose, talc, silica, aluminumhydroxide, calcium silicate and polyamide powders or mixtures of thesesubstances. Sprays can additionally contain the customary propellants,for example chlorofluorohydrocarbons.

Solutions and emulsions can contain the customary vehicles in additionto the active compound or compounds, such as solvents, solubilisingagents and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, especially cottonseed oil, groundnut oil, maize germ oil, oliveoil, castor oil and sesame oil, glycerol, glycerol-formal,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain the customary vehicles in addition to the activecompound or compounds, such as liquid diluents, for example water, ethylalcohol or propylene glycol, suspending agents, for example ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol esters and sorbitanesters, microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth, or mixtures of these substances.

The formulation forms mentioned can also contain colourants,preservatives and additives which improve the odour and flavour, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active end products should preferably be present inthe abovementioned pharmaceutical preparations in a concentration ofabout 0.1 to 99.5, preferably of about 0.5 to 95, % by weight of thetotal mixture.

The abovementioned pharmaceutical preparations can also contain otherpharmaceutically active compounds in addition to the compounds accordingto the invention.

The abovementioned pharmaceutical preparations are manufactured in theusual manner according to known methods, for example by mixing theactive compound or compounds with the vehicle or vehicles.

The active end products preparations can be administered locally,orally, parenterally, intraperitoneally and/or rectally, preferablyorally or parenterally, such as intravenously or intramuscularly.

In general, it has proved advantageous both in human medicine and inveterinary medicine to administer the active compound or compounds inamounts of about 0.5 to about 500, preferably 5 to 100, mg/kg of bodyweight every 24 hours, optionally in the form of several individualadministrations, in order to achieve the desired results. An individualadministration contains the active compound or compounds preferably inamounts of about 1 to about 250, especially of 3 to 60, mg/kg of bodyweight. However, it can be necessary to deviate from the dosagesmentioned and in particular to do so as a function of the nature andbody weight of the subject to be treated, the nature and the severity ofthe illness, the nature of the preparation and of the administration ofthe medicine, and the time or interval over which the administrationtakes place.

Thus, it can suffice in some cases to manage with less than theabovementioned amount of active end product, whilst in other cases theabovementioned amount of active end product must be exceeded. Theparticular required optimum dosage and the type of administration of theactive compounds can easily be decided by anyone skilled in the art, onthe basis of his expert knowledge.

The end products can be administered in the customary concentrations andpreparations together with the feed or with the feed preparations orwith the drinking water. By this means, it is possible to prevent,ameliorate and/or heal an infection by Gram-negative or Gram-positivebacteria and by this means to achieve a promotion of growth and animprovement in the utilisation of the feed.

The MIC values of some of the end products are indicated in the tablebelow.

As a comparison, corresponding MIC values for1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid ("norfloxacin"), which is disclosed in J. Med. Chem. 23, 1358(1980), have been indicated, it emerging that the end products aresuperior to the known compounds.

    __________________________________________________________________________    MIC (mcg/ml)                                                                            Example No.                                                         strain    1   2     3   5     6   7     8   10                                __________________________________________________________________________    E. Coli Neumann                                                                         ≦0.015                                                                     ≦0.015                                                                       ≦0.015                                                                     ≦0.015                                                                       ≦0.015                                                                     ≦0.015                                                                       ./. ≦0.015                     T 7       ≦0.015                                                                     ≦0.015                                                                       ≦0.015                                                                     ≦0.015                                                                       ≦0.015                                                                     ≦0.015                                                                       ≦0.015                                                                     0.025                             445/7     4   8     8   8     4   16    ./. 16                                Klebsiella 63                                                                           ≦0.015                                                                     0.03  0.03                                                                              0.03  0.015                                                                             0.06  ./. 0.125                             6179      0.03                                                                              0.03  ≦0.015                                                                     0.03  0.015                                                                             0.06  ./. 0.06                              Proteus 1017                                                                            ≦0.015                                                                     ./.   ./. ./.   0.06                                                                              0.125 ./. ./.                               Providencia 12012                                                                       ≦0.015                                                                     0.03  ./. ./.   0.03                                                                              ./.   ./. ./.                               12052     8   16    16  32    4   16    ./. ./.                               Staph. FK 422                                                                           0.25                                                                              0.25  0.25                                                                              0.25  0.025                                                                             0.5   0.06                                                                              ./.                               1756      0.25                                                                              0.5   0.25                                                                              0.5   0.5 0.5   0.06                                                                              ./.                               133       0.25                                                                              0.25  0.25                                                                              0.5   0.25                                                                              0.25  0.06                                                                              ./.                               Pseudom. Ellsworth                                                                      0.06                                                                              ./.   ./. ./.   ./. ./.   ./. ./.                               __________________________________________________________________________    MIC (mcg/ml)                                                                           Example No.                                                          Strain   17  12  13  14  17  19  20  21  22  Norfloxacin                      __________________________________________________________________________    E. coli Neumann                                                                        ./. ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     ./. ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     0.06                             T 7      ./. ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     ./. ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     ≦0.015                                                                     0.03                             455/7    ./. 8   8   2   ./. 1   1   1   2   16                               Klebsiella 63                                                                          ./. ≦0.015                                                                     ≦0.015                                                                     0.06                                                                              ./. 0.03                                                                              ≦0.015                                                                     0.06                                                                              0.03                                                                              0.125                            6179     ./. 0.06                                                                              0.06                                                                              0.25                                                                              ./. 0.03                                                                              0.03                                                                              0.03                                                                              0.06                                                                              0.25                             Proteus 1017                                                                           ./. 0.03                                                                              ≦0.015                                                                     0.125                                                                             ./. 0.03                                                                              ≦0.015                                                                     0.03                                                                              0.06                                                                              0.03                             Providencia 12012                                                                      ./. ≦0.015                                                                     ≦0.015                                                                     0.06                                                                              ./. 0.03                                                                              0.03                                                                              0.06                                                                              0.06                                                                              0.03                             12052    ./. 16  16  16  ./. 4   4   1   2   64                               Staph. F 422                                                                           ≦0.015                                                                     0.25                                                                              0.25                                                                              ./. ≦0.015                                                                     0.06                                                                              0.06                                                                              0.125                                                                             0.125                                                                             0.5                              1756     ≦0.015                                                                     0.25                                                                              0.25                                                                              ./. ≦0.015                                                                     0.06                                                                              0.06                                                                              0.125                                                                             0.125                                                                             1                                133      ./. 0.25                                                                              0.25                                                                              ./. ./. 0.06                                                                              0.06                                                                              0.06                                                                              0.125                                                                             0.5                              Pseud. Ellsworth                                                                       ./. 0.125                                                                             0.125                                                                             ./. ./. 0.125                                                                             0.25                                                                              ./. ./. 0.125                            __________________________________________________________________________     Agar dilution test/isosensitest medium                                   

We claim:
 1. A benzoic acid derivative of the formula: ##STR50## whereinR¹ is selected from the group consisting of H, Cl and F;and R² isselected from the group consisting of Cl and F; it only being possiblefor one of R¹ or R² to be F; excluding 2,4,5-trifluorobenzoic acid.